Hypertension is a risk factor for morbidity and mortality due to stroke, coronary artery disease, heart failure and chronic renal disease. Previous efforts to understand the pathophysiology of hypertension focused on the kidney and neurohumoral control of arteries. A unique aspect of this program project grant is focused on veins and the proposal that there are important differences exist in the neurohumoral control of veins and arteries normally and that abnormalities in neurohumoral control of veins contribute to the etiology of hypertension. Endothelin-1 (ET-1) and the sympathetic nervous system control venomotor tone and ET-1 and sympathetic nervous system activity is increased in deoxycorticosterone acetate (DOCA)-salt rat model of hypertension. Therefore, these studies will use DOCA-salt rats as the experimental model. The major goals of the project are to characterize how ET-1, sympathetic nerves and superoxide anions interact to alter venomotor tone and establish the relative importance of venomotor regulation in the development and maintenance of hypertension. There are four highly inter-related projects. Project 1 (Neurohumoral regulation of venomotor tone and vascular capacitance in hypertension) will focus on venomotor regulation in vivo. Project 2 (Endothelin peptides and sympathetic neurotransmission in arteries and veins in hypertension) will study hypertension associated changes in sympathetic neurotransmission to blood vessels in vitro. Project 3 (Differential control of mesenteric arteries and veins by sympathetic nerves in hypertension) will focus on the specific subgroups of sympathetic nerves that control arteries and veins and how the properties of these nerves are altered in hypertension. Project 4 (Signaling mechanisms in artiers and veins in hypertension) will study differences in receptor coupled signaling mechanisms in arterial and venous smooth muscle cells and how changes in these mechanisms contribute to hypertension. Four core units will support these projects. Core A will provide administrative support and overall supervision of the program. Core B will provide hypertensive animals and animal care support. Core C will provide analytical resources and Core D will provide support for tissue culture and gene transfer studies.